Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being so-named because of their prompt contractile action on extravascular smooth muscle tissue. The receptor for substance P is a member of the superfamily of G protein-coupled receptors.
The neuropeptide receptors for substance P (NK-1) are widely distributed throughout the mammalian nervous system (especially brain and spinal ganglia), the circulatory system and peripheral tissues (especially the duodenum and jejunum) and are involved in regulating a number of diverse biological processes.
The central and peripheral actions of the mammalian tachykinin substance P have been associated with numerous inflammatory conditions including migraine, rheumatoid arthritis, asthma, and inflammatory bowel disease as well as mediation of the emetic reflex and the modulation of central nervous system (CNS) disorders such as Parkinson""s disease (Neurosci. Res., 1996, 7, 187-214), anxiety (Can. J. Phys., 1997, 75, 612-621) and depression (Science, 1998, 281, 1640-1645).
Evidence for the usefulness of tachykinin receptor antagonists in pain, headache, especially migraine, Alzheimer""s disease, multiple sclerosis, attenuation of morphine withdrawal, cardiovascular changes, oedema, such as oedema caused by thermal injury, chronic inflammatory diseases such as rheumatoid arthritis, asthma/bronchial hyperreactivity and other respiratory diseases including allergic rhinitis, inflammatory diseases of the gut including ulcerative colitis and Crohn""s disease, ocular injury and ocular inflammatory diseases, is reviewed in xe2x80x9cTachykinin Receptor and Tachykinin Receptor Antagonistsxe2x80x9d, J. Auton. Pharmacol., 13, 23-93, 1993.
Furthermore, Neurokinin 1 receptor antagonists are being developed for the treatment of a number of physiological disorders associated with an excess or imbalance of tachykinin, in particular substance P. Examples of conditions in which substance P has been implicated include disorders of the central nervous system such as anxiety, depression and psychosis (WO 95/16679, WO 95/18124 and WO 95/23798).
The neurokinin-1 receptor antagonists are further useful for the treatment of motion sickness and for treatment induced vomiting.
In addition, in The New England Journal of Medicine, Vol.340, No. 3 190-195, 1999 has been described the reduction of cisplatin-induced emesis by a selective neurokinin-1-receptor antagonist.
The present invention relates to compounds of the general formula 
wherein
R1 is hydrogen or halogen;
R2 is hydrogen, halogen, lower alkyl or lower alkoxy;
R3 is halogen, trifluoromethyl, lower alkoxy or lower alkyl;
R4 and R4xe2x80x2 are each independently other hydrogen or lower alkyl;
R5 is lower alkyl, lower alkoxy, amino, hydroxy, hydroxy-lower alkyl, xe2x80x94(CH2)n-piperazinyl optionally substituted by lower alkyl, xe2x80x94(CH2)n-morpholinyl, xe2x80x94(CH2)n+1-imidazolyl, xe2x80x94Oxe2x80x94(CH2)n+1-morpholinyl, xe2x80x94Oxe2x80x94(CH2)n+1-piperidinyl, lower alkyl-sulfanyl, lower alkyl-sulfonyl, benzylamino, xe2x80x94NHxe2x80x94(CH2)n+1N(R4xe2x80x3)2, xe2x80x94(CH2)nxe2x80x94NHxe2x80x94(CH2)n+1N(R4xe2x80x3)2, xe2x80x94(CH2)n+1N(R4xe2x80x3)2, or xe2x80x94Oxe2x80x94(CH2)n+1N(R4xe2x80x3)2, wherein R4xe2x80x3 is hydrogen or lower alkyl;
R6 is hydrogen;
R2 and R6 or R1 and R6 may together be xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94, wherein R2 and R6 or R1 and R6, respectively, together with the two carbon ring atoms to which they are attached form a fused ring, with the proviso that n for R1 is 1;
n is independently 0-2; and
X is xe2x80x94C(O)N(R4xe2x80x3)xe2x80x94 or xe2x80x94N(O)xe2x80x94;
and to pharmaceutically acceptable acid addition salts thereof.
The compounds of formula I and their salts are characterized by valuable therapeutic properties. It has been surprisingly found that the compounds of the present invention are antagonists of the Neurokinin 1 (NK-1, substance P) receptor.
The present invention relates to compounds of the general formula 
wherein
R1 is hydrogen or halogen;
R2 is hydrogen, halogen, lower alkyl or lower alkoxy;
R3 is halogen, trifluoromethyl, lower alkoxy or lower alkyl;
R4 and R4xe2x80x2 are each independently other hydrogen or lower alkyl;
R5 is lower alkyl, lower alkoxy, amino, hydroxy, hydroxy-lower alkyl, xe2x80x94(CH2)n-piperazinyl optionally substituted by lower alkyl, xe2x80x94(CH2)n-morpholinyl, xe2x80x94(CH2)n+1-imidazolyl, xe2x80x94Oxe2x80x94(CH2)n+1-morpholinyl, xe2x80x94Oxe2x80x94(CH2)n+1-piperidinyl, lower alkyl-sulfanyl, lower alkyl-sulfonyl, benzylamino, xe2x80x94NHxe2x80x94(CH2)n+1N(R4xe2x80x3)2, xe2x80x94(CH2)nxe2x80x94NHxe2x80x94(CH2)n+1N(R4xe2x80x3)2, xe2x80x94(CH2)n+1N(R4xe2x80x3)2, or xe2x80x94Oxe2x80x94(CH2)n+1N(R4xe2x80x3)2, wherein R4xe2x80x3 is hydrogen or lower alkyl;
R6 is hydrogen;
R2 and R6 or R1 and R6 may together be xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94, wherein R2 and R6 or R1 and R6, respectively, together with the two carbon ring atoms to which they are attached form a fused ring, with the proviso that n for R1 is 1;
n is independently 0-2; and
X is xe2x80x94C(O)N(R4xe2x80x3)xe2x80x94 or xe2x80x94N(O)xe2x80x94;
and to pharmaceutically acceptable acid addition salts thereof.
The compounds of formula I and their salts are characterized by valuable therapeutic properties. It has been surprisingly found that the compounds of the present invention are antagonists of the Neurokinin 1 (NK-1, substance P) receptor.
The present invention provides the compounds of formula I and pharmaceutically acceptable salts thereof, the preparation of the above-mentioned compounds, medicaments containing them and their manufacture as well as the use of the above-mentioned compounds in the control or prevention of illnesses, especially of illnesses and disorders of the kind referred to earlier or in the manufacture of corresponding medicaments.
The most preferred indications in accordance with the present invention are those which include disorders of the central nervous system, for example the treatment or prevention of certain depressive disorders or emesis by the administration of NK-1 receptor antagonists. A major depressive episode has been defined as being a period of at least two weeks during which, for most of the day and nearly every day, there is either depressed mood or the loss of interest or pleasure in all, or nearly all activities.
The following definitions of the general terms used in the present description apply irrespective of whether the terms in question appear alone or in combination. As used herein, the term xe2x80x9clower alkylxe2x80x9d denotes a straight- or branched-chain alkyl group containing from 1-7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, t-butyl and the like.
Preferred lower alkyl groups are groups with 1-4 carbon atoms.
The term xe2x80x9clower alkoxyxe2x80x9d denotes a group wherein the alkyl residues are as defined above, and which is attached via an oxygen atom.
The term xe2x80x9chalogenxe2x80x9d denotes chlorine, iodine, fluorine and bromine.
The term xe2x80x9cpharmaceutically acceptable acid addition saltsxe2x80x9d embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, p-toluenesulfonic acid and the like.
Exemplary preferred compounds are those in which X is xe2x80x94C(O)N(R4xe2x80x3)xe2x80x94, wherein R4xe2x80x3 is methyl and R5 is xe2x80x94(CH2)n-piperazinyl, optionally substituted by methyl, and n is 0 or 1, for example the following compounds:
5-(2-chloro-phenyl)-2-(4-methyl-piperazin-1-yl)-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
5-(4-fluoro-2-methyl-phenyl)-2-(4-methyl-piperazin-1-yl)-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide or
5-(2-chloro-phenyl)-2-(4-methyl-piperazin-1-ylmethyl)-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide.
Further preferred are compounds in which X is xe2x80x94C(O)N(R4xe2x80x3)xe2x80x94, wherein R4xe2x80x3 is methyl nd R5 is xe2x80x94O(CH2)2-morpholinyl.
An example of such a compound is
5-(2-chloro-phenyl)-2-(2-morpholin-4-yl-ethoxy)-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amid.
Preferred are further compounds, in which X is xe2x80x94C(O)N(R4xe2x80x3)xe2x80x94, R4xe2x80x3 is methyl and R5 is xe2x80x94NH(CH2)n+1N(CH3)2, xe2x80x94(CH2)nxe2x80x94NH(CH2)n+1N(CH3)2 or xe2x80x94O(CH2)n+1N(CH3)2, wherein n is 1 or 2, for example the following compounds:
5-(2-chloro-phenyl)-2-(2-dimethylamino-ethylamino)-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
2-(2-dimethylamino-ethylamino)-5-o-tolyl-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
2-(2-dimethylamino-ethylamino)-5-(2-methoxy-phenyl)-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
2-(2-dimethylamino-ethylamino)-5-(4-fluoro-phenyl)-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
2-(2-dimethylamino-ethylamino)-5-(4-fluoro-2-methyl-phenyl)-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
5-(2-chloro-phenyl)-2-(3-dimethylamino-propoxy)-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
5-(2-chloro-phenyl)-2-(2-dimethylamino-ethoxy)-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
2-(2-dimethylamino-ethoxy)-5-o-tolyl-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
2-(3-dimethylamino-propoxy)-5-o-tolyl-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
2-(2-dimethylamino-propoxy)-5-(2-methoxy-phenyl)-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
2-(3-dimethylamino-propoxy)-5-(4-fluoro-2-methyl-phenyl)-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
2-(2-dimethylamino-ethoxy)-5-(4-fluoro-2-methyl-phenyl)-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide or
5-(2-chloro-phenyl)-2-[(2-dimethylamino-ethylamino)-methyl]-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide.
Further preferred are compounds, wherein X is xe2x80x94CON(R4xe2x80x3)2 and R4xe2x80x3 is methyl and R5 is SCH3, for example the following compounds:
2-methylsulfanyl-5-o-tolyl-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide or
5-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide.
Other preferred compounds are those, in which X is xe2x80x94CON(R4xe2x80x3)2 and R4xe2x80x3 is methyl and R2 and R6 or R1 and R6 are together xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94, wherein R2 and R6 or R1 and R6, respectively, together with the two carbon ring atoms to which they are attached form a fused ring, with the proviso that n for R1 is 1, for example the following compounds:
2-(4-methyl-piperazin-1-yl)-5-naphthalen-1-yl-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
2-(2-dimethylamino-ethylamino)-5-naphthalen-1-yl-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
2-(2-dimethylamino-ethoxy)-5-naphthalen-1-yl-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
2-(2-morpholin-4-yl-ethoxy)-5-naphthalen-1-yl-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide or
2-(3-dimethylamino-propoxy)-5-naphthalen-1-yl-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide.
Further preferred are compounds, wherein X is xe2x80x94N(R4xe2x80x3)C(O)xe2x80x94, R4xe2x80x3 is lower alkyl and R5 is xe2x80x94(CH2)n-piperazinyl optionally substituted by lower alkyl, xe2x80x94(CH2)n-morpholinyl, xe2x80x94NHxe2x80x94(CH2)n+1N(CH3)2 or xe2x80x94Oxe2x80x94(CH2)n+1N(CH3)2, for example the following compounds:
2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-[2-(4-methyl-piperazin-1-yl)-5-o-tolyl-pyrimidin-4-yl]-isobutyramide,
2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(2-piperazin-1-yl-5-o-tolyl-pyrimidin-4-yl)-isobutyramide,
2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(2-morpholin-4-yl-5-o-tolyl-pyrimidin-4-yl)-isobutyramide,
2-(3,5-bis-trifluoromethyl-phenyl)-N-[2-(2-dimethylamino-ethylamino)-5-o-tolyl-pyrimidin-4-yl]-N-methyl-isobutyramide,
2-(3,5-bis-trifluoromethyl-phenyl)-N-[2-(2-dimethylamino-ethoxy)-5-o-tolyl-pyrimidin-4-yl]-N-methyl-isobutyramide,
2-(3,5-bis-trifluoromethyl-phenyl)-N-[5-(2-chloro-phenyl)-2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yl]-N-methyl-isobutyramide or
2-(3,5-bis-trifluoromethyl-phenyl)-N-[5-(2-chloro-phenyl)-2-(2-dimethylamino-ethylamino)-pyrimidin-4-yl]-N-methyl-isobutyramide.
The present compounds of formula I and their pharmaceutically acceptable salts can be prepared by methods known in the art, for example, by processes described below, which process comprises
a) reacting a compound of formula 
xe2x80x83with a compound of formula 
xe2x80x83to a compound of formula 
xe2x80x83wherein
R1-R5 and n have the significances given above, or
b) reacting a compound of formula 
xe2x80x83with a compound of formula 
xe2x80x83to give a compound of formula 
xe2x80x83wherein
R1-R5 and n have the significances given above, and optionally
c) modifying one or more substituents R1-R5 within the definitions given above, and/or if desired, converting the compound obtained into a pharmaceutically acceptable acid addition salt.
In accordance with process variant a), a compound of formula II, for example [5-(2-chloro-phenyl)-2-methylsulfonyl-pyrimidin-4-yl]-methyl-amine is deprotected with KHMDS (potassium hexamethyldisilazide) in THF at 0xc2x0 for 1 h, and a compound of formula III, for example 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride, is added and the mixture is stirred at room temperature. A typical solvent is N,N-dimethylformamide. The desired compound of formula I-1 is obtained in good yields.
Process variant b) describes the reaction of a compound of formula IV with a compound of formula V to a compound of formula I-2. The reaction is carried out in conventional manner, for example in a solvent, such as dichloromethane in presence of NEt3, EDCI (N-(3-dimethylaminopropyl)-Nxe2x80x2-ethyl-carbodiimide hydrochloride) and HOBT (1-hydroxy-benzotriazole). The mixture is stirred for about 12 hs at room temperature. The desired product is obtained after purification in good yields.
The salt formation is effected at room temperature in accordance with methods which are known per se and which are familiar to any person skilled in the art. Not only salts with inorganic acids, but also salts with organic acids came into consideration. Hydrochlorides, hydrobromides, sulphates, nitrates, citrates, acetates, maleates, succinates, methansulphonates, p-toluenesulphonates and the like are examples of such salts.
The following schemes 1-6 describe the processes for preparation of compounds of formula I in more detail. The starting materials of formulae III, VIII, IX, XII, XIII, XVI, XVII and XXII are known compounds and may be prepared according to methods known in the art.
In the schemes the following abbreviations have been used:

The substituents R1-R6 are given above.
A is an amine group, such as amino or piperazinyl optionally substituted by lower alkyl, morpholinyl, imidazolyl, piperidinyl,benzylamino or xe2x80x94NHxe2x80x94(CH2)n+1N(R4xe2x80x3)2, and B is lower alkoxy, xe2x80x94Oxe2x80x94(CH2)n+1-morpholinyl, xe2x80x94Oxe2x80x94(CH2)n+1-piperidinyl or xe2x80x94Oxe2x80x94(CH2)n+1N(R4xe2x80x3)2; 
The substituents are given above. 
The substituents R1-R6 are given above.
A is an amine group, such as amino or piperazinyl optionally substituted by lower alkyl, morpholinyl, imidazolyl, piperidinyl, benzylamino or xe2x80x94NHxe2x80x94(CH2)n+1N(R4xe2x80x3)2. 
The substituents R1-R6 are given above.
A is an amine group, such as amino, piperazinyl, optionally substituted by lower alkyl, morpholinyl, imidazolyl, piperidinyl,benzylamino or xe2x80x94NHxe2x80x94(CH2)n+1N(R4xe2x80x3)2, and B is lower alkoxy, xe2x80x94Oxe2x80x94(CH2)n+1-morpholinyl, xe2x80x94Oxe2x80x94(CH2)n+1-piperidinyl or xe2x80x94Oxe2x80x94(CH2)n+1N(R4xe2x80x3)2;
As mentioned earlier, the compounds of formula I and their pharmaceutically usable addition salts possess valuable pharmacological properties. It has been found that the compounds of the present invention are antagonists of the Neurokinin 1 (NK-1, substance P) receptor.
The compounds were investigated in accordance with the tests given hereinafter.
The affinity of test compounds for the NK, receptor was evaluated at human NK, receptors in CHO cells infected with the human NK1 receptor (using the Semliki virus expression system) and radiolabelled with [3H]substance P (final concentration 0.6 nM). Binding assays were performed in HEPES buffer (50 mM, pH 7.4) containing BSA (0.04 %) leupeptin (8 xcexcg/ml), MnCl2 (3mM) and phosphoramidon (2 xcexcM). Binding assays consisted of 250 xcexcl of membrane suspension (1.25xc3x97105 cells/assay tube), 0.125 xcexcl of buffer of displacing agent and 125 xcexcl of [3H]substance P. Displacement curves were determined with at least seven concentrations of the compound. The assay tubes were incubated for 60 min at room temperature after which time the tube contents were rapidly filtered under vacuum through GF/C filters presoaked for 60 min with PEI (0.3%) with 2xc3x972 ml washed of HEPES buffer (50 mM, pH 7.4). The radioactivity retained on the filters was measured by scintillation counting. All assays were performed in triplicate in at least 2 separate experiments.
The affinity to the NK-1 receptor, given as pKi, is in the scope of 8.00-9.30 for the preferred compounds. Examples of such compounds are
The compounds of formula I as well as their pharmaceutically usable acid addition salts can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. The administration can, however, also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.
The compounds of formula I and their pharmaceutically usable acid addition salts can be processed with pharmaceutically inert, inorganic or organic excipients for the production of tablets, coated tablets, dragees and hard gelatine capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc can be used as such excipients e.g. for tablets, dragees and hard gelatine capsules.
Suitable excipients for soft gelatine capsules are e.g. vegetable oils, waxes, fats, semi-solid and liquid polyols etc. Suitable excipients for the manufacture of solutions and syrups are e.g. water, polyols, saccharose, invert sugar, glucose etc. Suitable excipients for injection solutions are e.g. water, alcohols, polyols, glycerol, vegetable oils etc. Suitable excipients for suppositories are e.g. natural or hardened oils, waxes, fats, semi-liquid or liquid polyols etc.
Moreover, the pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
The dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of oral administration a daily dosage of about 10 to 1000 mg per person of a compound of general formula I should be appropriate, although the above upper limit can also be exceeded when necessary. Preferred are dosages of 20 mg to 500 mg per day. Further preferred are dosages of 50 mg to 200 mg per day.